It is a process occurring in the walls of large and medium sized elastic arteries where an irregular thickening of the wall occurs, due to deposition of lipids, smooth muscles, connective tissues and other cells. Lesion is called an atheroma and the process is called atherosclerosis. There are several theories to explain how this process occurs. Out of them, the,”REACTION TO INJURY”, theory is the most accepted one.

There are so many ways, which I have mentioned later, where endothelium of the vessel can get damaged or injured. Once an endothelium is injured, it leads to secretion of various cytokines which would activate platelets and also it would increase the expression of VCAM-1 where platelet adhesion will take place. Mean while lipids will also get accumulated. Accumulated lipids will get oxidized producing oxidative species. When lipoproteins, specially LOW DENSITY LIPOPROTEINS (LDL) get accumulated, they will be altered by the oxidative species generated.

While all these are going on damaged endothelial cells will secrete cytokines which would stimulate Monocytes to migrate into intima. Ingestion of altered lipo proteins will make them to loose their function and become FOAM cells.

With the activation of T cells, various cytokines will be released (Eg:- IFN- gamma) which would in turn stimulate macrophages, endothelial cells and smooth muscle cells. Then from these cells who got activated various cytokines ( Eg:- PDGF, FGF,TGF-alpha) will be released where they recruit smooth muscle precursor cells into intima, from either media or from circulating precursors. Ultimately smooth muscle cell proliferation, along with connective tissue proliferation and deposition of lipids both extracellular and extracellular will occur.

This topic can be discussed without any limit for any number of days,weeks or for years. This is a that much vast area. But today I am going to tell you something about vasculitis from a point of view of an undergraduate medical student, who need a way to keep things in an orderly fashion, before they more on to very sophisticated, complex details beyond the level of an undergraduate.

Vasculitis is a general term for inflammation in the vessel wall. Signs and symptoms of these conditions greatly vary depending on the vasculature of which system they affect or affect most. If something to be kept in mind, we need to develop an order. To develop an order, we need to categorize properly.

There are various categories being introduced. But as Undergraduates, there are certain important vasculitis conditions we must know and I have used my own way of classifying as follows. You can make your own classid=fication and find your own way to make things easy for you, if you are willing to read.

Namely Giant cell arteritis, Takayasu arteritis, Polyarteritis nodosa, Kawasaki disease, Microscopic polyangitis, Wegener’s disease, Churg – strauss syndrome, Systemic Lupus Erythromatosis (SLE), Immunoglobulin A mediated vasculitis/nephropathy and vasculitis conditions caused by infections are very important and carries a great importance. So I am going to talk about them according to the ABOVE SHOWN CLASSIFICATION, elaborating following areas in each vasculitis condition;

There are two main vasculitis conditions occurring in LARGE TO MEDIUM SIZED MUSCULAR ARTERIES. They are GIANT CELL ARTERITIS and TAKAYASU ARTERITIS. The main demo-graphical difference between these two is, giant cell arteristis mostly occur in people above 50 years of age and Takayasu occurs in people who are younger than 50 years.

Giant cell arterits mostly occurs in Aorta and its called Giant cell Aortitis. It is also occuring in temporal arteries leading to Temporal arteritis. This begets a severe, sudden, intermittent, unilateral, throbbing type Headache which mimics a migraine attack. When diagnosing a migraine patient taking this into consideration would be critical in managing the patient. Granulomas are found, but it is NOT a narcotizing lesion. The key morphological feature is “Medial granulomatous inflammation”. There is fragmentation of internal elastic lamina, where inflammation is centred with the ivasion of mono nuclear cell aggregates.

Takayasu arteritis mainly occurs in Arch of Aorta, often with great vessels . It is also characterized by granuloma formations. In contrast to above, here we can see patchy necrosis of media (it is considered rare). Key morphologica feature is intimal hyperplasia along with perivascular cuffing of mononuclear cells around vasa vasorum, which supplies blood to media. This would compromise the oxygen and nutrient supplies to media and media will be subjected to destruction. This is repleted by GIANT CELLS, and patchy medial necrosis occurs. Even though this mostly involves the ARCH OF AORTA and the Great vessels, this can involve or progress in to any part of the aorta. Depending on the parts involved, clinical picture is determined. When Arch and the great vessels are involved, as the lumen narrows, the blood supply to upper extremities are limited. This will lead to diminished pulses in upper limbs. This is typically called,”Pulse less Disease”. if it involves the lower part of aorta, it can lead to claudication. If pulmonary vasculature is involved, it would lead to pulmonary hypertension and if renal vasculature is involved, it would lead to hypertension.

Vasculitis conditions occurring mainly in small to medium sized arteries are caused by 2 main mechanisms. One is Immune-complex mediated and the other is Anti endothelial cell antibodies mediated. There is a major difference between these two conditions with respect to the age where we can observe these conditions most. Polyarteritis nodosa occurs typically in young adults, who are less than 40 years with a male preponderance of 2:1 (Male:Female). Kawasaki disease occurs mainly in children who are 4 years or younger than that.

Polyarteritis nodosa is a vaculitis condition where there is NO granuloma formation, but there is a Necrosis ( this is called fibrinoid necrosis, a special type of a necrosis occurig in blood vessels). This necrosis occurs mainly at the branching points of a vessels and it will be circumferential. Once the necrosis occurred, the lumen will be narrowed and as the endothelium is damaged, it would be prone to formation of a thrombus. Both these will cause reduced blood supply to the level below the narrowing causing ulceration, ischemia, infarction and hemorrhages. Depending on the system affected the clinical picture would vary. The MOSTLY AFFECTED SYSTEM IS RENAL system. Renal arteries mainly at the branching point from the aorta, are narrowed and the tissue perfusion is reduced. As a result rapidly progressing hypertension and hematuria can occur. Next in line is the heart and then the Gastro-intestinal system. If the vasculature of the Gastro-intestinal system is involved, we can expect the patient to have bloody stools and abdominal pain.

Kawasaki disease is the leading cause of Myocardial infractions in childhood which is mediated by Anti Endothelial Cell Antibodies. The morphological features are more or less the similar to what happens in Polyarteritis Nodosa. Due to luminal narrowing because of Fibrinoid necrosis, and thrombus formation again because of the fibrinoid necrosis, it leads to ischemia and ultimately to infarction.

When moving on to vasculitis conditions occurring in small arteries to arterioles and capileries, again there are two main ways where we can make a distinct. Almost every condition mentioned under this topic are caused by immune complexes or else immune mediated. but in one category, these immune cells are sparse in the circulation. Therefore they are called ,”Pauci-immune” conditions, and in the other category immune coplexes are abundantly found in circulation.

Pauci-immune group consits of 3 main diseases where the pathologand morphoogy is more or less similar to Polyarteritis Nodosa with few exceptions. In all of these conditions a factor called, Anti Neutrophil Cytoplasmic Antibodies (ANCA) are present. There are two types of ANCA as p-ANCA and c-ANCA. C-ANCA is predominantly found in Wegener’s granulomatosis (Microscopic polyangitis with gralnulomatosis) and p-ANCA is predominantly present in Microscopic polyangitis.

Microscopic polyangitis is carrying similar morphology and pathology to Polyarteritis nodosa, except that they affect mainly capillaries and the fibrinoid necrosis occuring is NOT CIRCUMFERENTIAL; it is rather a SEGMENTAL TYPE NECROSIS. Here glomeruli are directly feted, and if something is destroying glomeruli of a nephrone, it’s ability to regenerate is completely compromised. Microscopic Polyangitis can be a feature of many diseases such as Henoch-Schonlein purpura, essential mixed cryoglobulinemia, etc. Depending on the system/organ invloved again as in polyarteritis nodosa you can work out the clinical features such as haemoptysis, heaturia, bloody stools, proteinuria, abdominal pain etc.

Granulomatosis with polyangitis (eralier Known as “Wegener’s Granulomatosis), name it self implies that it is a condition where polyangitis occurs with granulomatosis. Morphology and the pathology will be very much similar to Microscopic polyangitis, but this time with a granulomatosis. Still they are affecting capillery systems (same as Microscopic polyangitis), but this time they are more concentrated on the repiratory system; Lungs and upper airways mostly. So there will Necrotizing granuolomas in upper airways with persistant pneumonitis, chronic sinusitis with mucosal ulceration of nasopharynx, etc . It also affects renal vasculature. It has a classical morphological feature with regard to renal aspect called,”Focal, Necrotizing, Crescentinc glomerularnephritis”.

Churg-strauss syndrome also carries similar morphology to both above conditions, it differs from microscopic polyangitis as it shows granulomatosis with eosinophilia, and from Wegener’s disease as this time they have eosinophilia. This condition also concentrates more on respiratory tract. In addition to above mentioned clinical features under Wegener’s, we have to add ASTHMA to churg-strauss as eosinophilia in respiratory tract can lead to asthma. One of the application where Leukotriene receptor antagonists can be used as drugs is this condition, as in this condition it is being reported that leukotriene receptors have been triggered in churg strauss syndrome.

I hope I could be some assistance to figure out that its not that difficult to keep vasculitis in mind. I know there are so many other things to be included under these. But every leap begins with a single step. Try to find your own way. Then first make a STRUCTURE/MOCK-UP/A SKETCH. Then start adding details in a systematic way. It would make your work efficient and easy to recall anything you want ASAP…!!

People are often mislead by these two disease conditions where they are completely different from each other. I am going to talk about these two disease conditions in comparison two each other under following topics;

Definition

Etiology

Pathogenesis

Morphology

Clinical aspect

Rheumatic Heart Disease (RHD) is a multi system involved, immunologically mediated followed by a group A beta haemolytic bacterial infection. It is not a direct infection on heart.

In contrast, Infective Endocarditis (IE) is a direct infection on heart valves or mural endocardium which leads to formation of large, friable vegetations containing thrombotic debris, fibrin, dead organisms and white blood cells, and live causative organisms, which would erode and destroy the surrounding tissue. This is a direct invasion of the heart.

Moving on to the etiology of Rheumatic Heart Disease (RHD), the main causative organism is a group A beta haemolytic bacteria ( mainly streptococci). Usually it is preceded by a streptococcal pharyngitis. But there are incidents where a streptococcal skin infection can also give rise to RHD. Mainly it is associated with people who are having poor hygiene, low economic states.

Rheumatic Heart Disease (RHD) has two forms as acute RHD and chronic RHD. Both are accounted by the same organism, but the rate of disease progression, duration of disease existence and clinical features are different. Let’s talk about them under clinical aspect.

Infective Endocarditis (IE) is having two types as Acute IE and Subacute IE. Causative organisms are bit different from one to another. In acute IE, mainly a valve which was previously normal will be infected by a highly virulent organism. The most accounted causative organism is Staphylococcus aureus. Subacute IE mainly occur in people with defective valves due to one or more of following reasons;

A valve damaged by Rheumatic heart disease with scarring

Bicuspid aortic valve

Prosthetic valve

Surgery done in heart to rectify an anatomical defect in heart or in valves, acquired or congenital.

Degenerative calcific valvular stenosis

Subacute IE mostly occurs from less virulent organisms such as Streptococcus viridans who are normal flora of oral cavity. Predisposing conditions which would lead to this type would be dental surgeries, surgeries in gut, intravenous drug abuse, valvular abnormalities, etc. A condition which has the potential to give rise to a bacteremia or a fungemia can cause subacute IE.

Apart from above, HACEK group, fungi, virus, enterococci can infect endocardium. Even though IE is mostly occurring in left side of the heart, in groups like Intravenous drug abusers right side of the heart also can be infected.

Rheumatic Heart disease almost always affect the left side of the heart. But disease progression can deteriorate the function and anatomy right side of the heart.

Moving on to the pathology, Rheumatic Heart disease is mainly an immunologically mediated disease.What happens is, when streptococci organisms invade, body starts fighting back. Antibodies are made against mainly strptococcal M protein and hyaluronic acid. These antibodies will be mislead as these antigens can mimic self antigens in the body in places like heart, joints, etc. Not only that CD4+ T cells will get activated as a defense mechanism and they will secrete several cytokines which would ultimately activate ,macrophages which would lead the destruction. This process is augmented by neutrophil activation mediated by antibodies via classical pathway. So it is obvious that heart does not suffer a direct invasion of organisms.

Morphology of RHD is easy to remember if someone knows the pathogenesis. In acute RHD, there will be foci containing fibrin thrombotic debris, neutrophils and activated macrophages within endocardium, myocardium or pericardium which can cause “Pancarditis”. These are called Aschoff Bodies. Activated macrophages are seen as large cells with condensed and ribbon like chromatin which would be seen as a caterpillar (hence called catepillar cells) which are known as antischkow cells. Due to the inflammation in the endocardium valves and chordate tendinae will be subjected to fibrinoid necrosis. On the top of these necrotic foci, bland, non suppurative, small, warty vegetation along the margins of the closure of valves will be developed. These are called varrucae bodies. Subendocardial lesions are made worse due to the frequent damage from regurgitation jets (initially there is a regurgitation) which would lead to irregular thickening of the endocardium called “McCallum Plaques”.Acute RHD could be having pancarditis, pericardial rub serofibrinous or fibrinous pericarditis. In chronic RHD, due to constant damage to valves and the chordate tendinae, these will be fibrotic and damaged. There will be shortening of tendinae leading to inadequate closure of the valves leading to regurgitation. Also there will be fusion of the commissures of the valves and the chordate tendinae, leading to stenosis, which would give rise to a fish mouth appearance in the mitral valve. Virtually the only reason for mitral valve stenosis is RHD.

Moving on to the pathogenesis of Infective Endocarditis (IE), basically in acute IE, as the organism is highly virulent, they can directly damage the endocardium and expose the tissue factors and vonWilbrand factors which would lead to activation of platelets. In turn plates will be aggregated on top of these leading to formation of massive, suppurative, friable masses ON THE TOP OF THE VALVES with dead cells, fibrin, and causative organism. More the platelets aggregate, more the size of the vegetation. And more the size of the vegetation, higher the number of organisms established within it. In Subacute IE, a granulation tissue can be seen at the bottom of the lesion which would indicate the features of healing. Finally if this is healed, it would be by fibrosis.

Moving on to the clinical aspect, Acute Rheumatic Heart Disease is often easily diagnosed. Main factors to establish a diagnosis would be ;

Evidence of a preceding streptococcal infection

with two or more from the MAJOR CRITERIA (Migratory poly arthritis, pancarditis, subcutaneous nodules, sydenham chorea, erythema marginatum)

or with one from the MAJOR CRITERIA and two or more from MINOR CRITERIA (Fever, arthralgia, previous RHD, Acute phase reactants, prolonged PR interval)

In acute RHD, rheumatoid factor would be positive. There are conditions it is negative too. Also there will be streptolysin O or DNase B antigen circulating the blood stream, which would help in final diagnosis. But the clinical diagnosis would be critical rather than depending on the investigations.

Rheumatic heart Disease, even if it is easy to diagnose, the patient might not present to a doctor at initial stage as the disease progression may take place over many years. This is a major draw back.

Infective endocarditis is bit difficult to diagnose mainly due to 3 reasons;

Prior antibiotic therapy/ Antibiotic abuse

As the vegetation is large, organisms are deeply buried in the lesions, without being released into the blood stream.

difficulties in isolating the organism ( eg :- many etiological agents are causing it. If a correct culture is not done, a growth cannot be expected)

Few clinical features are;

Splinter / subungual hemorrhages – due to micro-thrombo embolism from the friable vegetation.

Osler’s nodes – Subcutaneous nodules in the pulp of the digits.

Janeway sign – erythematous or hemorreghic lesions on the palms and soles.

Roth spots – retinal hemorrhages

These are the facts which you can establish a distinct difference between these two conditions. If you know the basics, it would be easy to work them out, rather than keeping everything in memory.

Abnormal permanent dilation of part of aortic wall, with intact walls which are attenuated and thinned out ,due to a congenital cause or an acquired cause is Known as an Aortic Aneurysm. There are many causes which would lead to aneurysms, as I have discussed in my other blog post called, :Quick look at Aneurysms and Dissection.

Here we are focussing mainly on acquired causes. Out of both congenital and acquired causes, two most contributed causes for aortic aneurysms, especially in abdominal aorta, is atherosclerosis and Hypertension. Tertiary syphilis is another rare cause.

Atherosclerosis —–> Intimal thickening —-> increase the distance of oxygen and nutrient diffusion form the blood in lumen to inner media

All above ultimately leads to Medial ischemia.In response to medial ischemia, following occurs,

Loss of smooth muscles

Increased degradation of the matrix

Defective synthesis of matrix proteins

increased synthesis of amorphous matter in the matrix (eg :- glycosaminoglycans) which would further apprehend the vascular integrity.

Aortic aneurysms are mainly either thoracic or abdominal. In Abdominal aneurysms, the patient is mainly asymptomatic and most of the times, it is discovered by accident during examination, or patients present as follows;

Rupture of an abdominal aortic aneurysm leading to massive hemorrhage into abdominal cavity which begets unbearable pain.

Due to Impingement of the aneurysm on adjacent structures which would give rise to different signs and symptoms (Eg:- Impingement on Ureters cause difficulty in passing urine)

Inadequate supply of blood to lower limbs, kidneys, gastro intestinal tract as the supply for these originate from the vessels branching from aorta.

Embolism from atheroma or mural thrombi occurring in the aneurysm.

In contrast Thoracic aneurysms are clinically detected as they have direct complications such as;

Impingement on recurrent laryngeal nerve leading to persistent dry cough

Impingement on thoracic vertebrae leading to erosion

Impingement on esophagus causing dysphagia (difficulty in swallowing)

Due to encroachment on lungs and airways, patient feels difficulty in breathing.

Aortic Dissections occur mainly due to hypertension. In contrast to aneurysms, Dissections have a distinct breach in the vessel wall, which leads to accumulation of blood, from the intravascular space between the laminar planes of media. This forms a blood filled channel within the media and blood do not communicate with the outside of the vessel as in false aneurysms.

Although even if we say there is a breach in the vessel wall, aortic dissections sometimes can occur without any intimal tear. Aorta is a large artery. It has a very large Tunica media. This layer is so thick, that small blood vessels called, “Vasa Vasorum”are present to supply blood to this layer to provide their nutritional and oxygen requirements. During hypertension due to medial thickening in the arterioles (Quick look at Pathology in hypertension) and loos of their integrity, these can rupture leading to accumulation of blood within the laminar planes of media of aorta.

Aortic dissections are mainly classified in to 2 TYPES depending on the part of the aorta involved.

Type A – includes Proximal dissections involving only ascending aorta or both in ascending and descending aorta.

Type B – Includes distal dissections involving descending aorta.

The classic clinical presentation of an aortic dissection is the sudden and abrupt onset of an unbearable excruciating pain from anterior aspect of chest, radiating to the back between the scapulae. This will move down with the progression of the dissection downwards. the most common cause of death would be the collection of blood in cavities such as pericardial, peritoneal and pleural spaces.

Aneurysms are permanent and abnormal dilation of a part of a blood vessel or heart due to an attenuated intact arterial wall, or thinned out wall of a heart, mainly ventricles. This is also known as a “True aneurysm”. The difference between a true and a false aneurysm is the intact wall in a true aneurysm. A false aneurysm is actually formed due to a defect in vascular wall, which leads to extra-vascular hematoma which freely communicates with the inside of the vessel. This is formed when blood is contained by the surrounding connective tissue after a complete breach in the vascular wall.

Eg :- as an acute complication after a Myocardial infarction, Cardiac rupture can occur. The blood in ventricles will be escaped into the pericardial space and the pericardial adhesions can limit this breach to a single focus.

Due to constant hemaodynamic stress a vessel wall is facing, it is in a continous process of synthesizing, degrading and remodelling/repairing the connective tissue. Any defect in this cycle would disrupt the intergrity of the vessel wall and lead to an aneurysm. All these reasons can be categorized mainly in to 3 main topics, as follows;

Increase degradation normally occurs when there is an inflammation going on in the wall. During atherosclerosis abnormal activity of macrophages will lead to increased levels of Matrix Metello Proteases(MMP) which would accelerate the degradation of vascular wall, over the synthesis. Also Production of certain inflaaotory cytokines will lead to stimulation of macrophages to release MMPs. Vasculitis is another example

Weakening of the vascular wall due to loss of smooth muscles or disposition of non collagenous/elastic substances. (Explained in Quick look at Aortic aneurysms and dissections)

In contrast to aneurysms, Dissections have a distinct breach in the vessel wall, which leads to accumulation of blood, from the intravascular space between the laminar planes of media. This forms a blood filled channel within the media and blood do not communicate with the outside of the vessel as in false aneurysms.

Although even if we say there is a breach in the vessel wall, aortic dissections sometimes can occur without any intimal tear. Aorta is a large artery. It has a very large Tunica media. This layer is so thick, that small blood vessels called, “Vasa Vasorum”are present to supply blood to this layer to provide their nutritional and oxygen requirements. During hypertension due to medial thickening in the arterioles (Quick look at Pathology in hypertension) and loos of their integrity, these can rupture leading to accumulation of blood within the laminar planes of media of aorta.

Normal cutoff values for blood pressure are 120/80 mmhg (systolic/diastolic). A person with sustained and persistent elevated blood pressure levels than the cutoff values is said to be having Hypertension.

Generally hypertension is categorized into two depending on the etiology as follows;

Primary Hypertension (Essential Hypertension)

Secondary Hypertension

Primary hypertension is said to be developing mainly due to 2 reasons. First is the genetic make- up. It is said that familial aggregation or the genetic make up would explain the occurrence of hypertension among twins. Second would be the vascular causes which would result in vasoconstriction. It could be an inbuilt cause which would stimulate constriction of vessels, or stimuli from outside such as smoking, obesity, stress, etc.

Secondary hypertension develops as a result of malfunction in another system. Depending on the etiology, causes for above, can be discussed under 4 main categories;

Renal

there are 3 main factors which would influence in increase in blood pressure such as activation of renin-angiostensin-aldesterone system, retention of sodium and water and Release of vasopressor materials. (Discussed mainly under “Quick look at physiology of Blood pressure regulation”)

There are various pathological changes occurring in hypertension in various organs. Many of these can be explained using the basic changes occurring in blood vessels, specially in arterial system.

In hypertension, due to increased haemodynamic stress, degenerative changes occurring in the large and small sized arteries will lead mainly to atherosclerosis. Also it would lead to aortic dissection, cerebrovascular hemorrhages and aneurysms.

Many of the pathological changes occurring in other oragns can be expalined using the changes occuring in arterioles.

Hyaline arteriolosclerosis

Hyperplastic arteriolosclerosis

Due to gradual elevation of blood pressure, over a long period would cause degenerative changes in the endothelial cells, which would lead to leakage of plasma proteins in to the intimal layer, causing aggregation of pink, glass like proteinacious material in the intimal layer of blood vessels, leading to intimal thickening, which would in turn cause luminal narrowing. Along with this as there would be an increase in synthesis of matrix of smooth muscle cells, in the Tunica media as a response to increased haemodynamic stress also contributes for luminal narrowing. These changes are called“Hyaline arteriolosclerosis”. Normally these changes occur in patients who have “Benign hypertension”, which develops slowly and gradually over years. These changes are mostly widespread and affects almost all the organs.

If the blood pressure suddenly and markedly elevated over 200/140mmhg, it is called “Malignant Hypertension”. Most acute change expected would be fibrinoid necrosis of blood vessels, due to marked increase in blood pressure. This would cause leakage of massive amount of fluid out in to the organs causing edema. If patient suffers from this type elevations in blood pressure, for a reasonable amount of time to call it a chronic condition, arterioles will show an adaptation where concentric laminated thickening of smooth muscles occurs with re-duplication of basement membranes. This would mimic the arrangement of an onion-skin. Therefore it is also called an Onion-Skin type thickening. These changes are known as “Hyperplastic Arteriolosclerosis”.

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Medicine is a field which grows faster. Yet the fundamentals you learn would be the laying the foundation, upon which you add the complex facts. So learning your basics, will decide how good your skills as a Doctor going to be..!!